14-Hydroxymorphinans, including such "nal" compounds as naloxone, naltrexone, and nalbuphine are important morphine derivatives due to their behavior as potent analgesics and/or narcotic antagonists. See U.S. Pat. No. 3,254,088 (naloxone); U.S. Pat. No. 3,332,950 (naltrexone); and U.S. Pat. No. 3,393,197 (nalbuphine). Among the prior synthetic routes to the preparation of these pharmaceuticals have been processes which utilize thebaine as a starting material. However, thebaine-based syntheses are not entirely satisfactory for a number of reasons. For example, thebaine is in limited supply and its cost is high, thereby contributing to high cost of the noroxymorphone and the 14-hydroxymorphinans derived from it.
Because of the scarcity and high cost of thebaine, efforts have been made in the art to devise methods for the synthesis of noroxymorphone from compounds in more plentiful supply than thebaine, for example morphine.
To synthesize noroxymorphone from morphine, the tertiary amine at the 17 position must be converted to a secondary amine via demethylation by some method; a hydroxyl group must be introduced at the 14 position; the hydroxyl group at the 6 position must be converted to a ketone; and the cycloalkene double bond must be reduced. However, the 3-hydroxyl group must survive the multiple reaction and purification steps and so must be protected. The protective group must be substantially uneffected by the reactions necessary to carry out these conversions, including extremely low pH reaction conditions, for example, less than 1.0 in one step. Yet the protecting group must be easily removable to restore the hydroxyl group when desired.
Moreover, all of these reactions, whether converting or protecting, must each be capable of producing high yields so that the overall yield of the multistep synthesis will be relatively high and the economics of producing noroxymorphone will not be adversely affected.
The present invention supplies these needs. It has been found that the 3-hydroxyl group, which is phenolic, can be protected by a carbonate, which will, surprisingly, survive the multiple reaction steps necessary to complete the conversion. It has been heretofore reported that carbonates provided only "marginal" protection to phenolic hydroxyl groups when exposed to pH conditions of less than 1. (See Greene, Protective Groups in Organic Synthesis.) However, in the present invention a carbonate group does protect the 3 position hydroxyl group under such conditions.
Advantageously, the same reaction that adds the carbonate to the 3 position produces a carbamate protecting group at the 17 position from the secondary amine, thus fulfilling two needs through one reaction. Additionally, the reaction step does not affect, to any substantial degree, the second hydroxyl group, so it can later be converted to a ketone. This advantageous discovery allows for a novel, economical route to synthesize noroxymorphone, in which a 14-hydroxyl group can be introduced using a peracid.